The burden of disease and negative economic impact of tobacco addiction on society is staggering. It is predicted that ~0.6 billion current smokers worldwide will die from smoking-related illnesses, such as chronic obstructive pulmonary disorder (COPD), lung cancer, and cardiovascular disease. The development of efficacious smoking cessation aids is considered the most cost-effective intervention possible within a modern health-care system. Although clinically efficacious, current smoking cessation agents have very limited utility. Indeed, there is considerable risk of relapse even when treated with the most efficacious medications currently available, Chantix and Zyban, which must also now carry "black box" warnings on their labeling because of reported serious mental-health events associated with their use. Pharmacotherapy is therefore an effective strategy to aid smoking cessation efforts, but there is a pressing need to develop safer and more effective therapeutics. Product Development Partnerships (PDPs) are a collaborative effort between academia, the pharmaceutical industry and charitable organizations that seek to discover, develop and deliver new medicines. PDPs bridge the gap between research and development for diseases for which there has traditionally been low priority in industry to develop effective therapeutics. The major advantage of the PDP mechanism for therapeutic development for smoking cessation with Scripps Florida as the Managing Partner (MP) is that it takes full advantage of our core mission at TSRI-Scripps Florida to develop medications to aid smoking cessation and combines this expertise with the scientific and financial resources of PDP partners. Therapeutics will include small molecules (novel and re-purposed, RNAs, peptides, antibodies, and novel formulations and delivery mechanisms). During the UH2 phase of the MITD, we will thoroughly explore the feasibility of establishing a successful PDP for the generation of new smoking cessation products. During the UH3 phase we will execute on the Milestones described below. The Milestones achieved during the UH2 phase of the MITD PDP are;1) Construct a searchable bioinformatic database to prioritize targets for therapeutic development. We will then report our findings using the database, along with all available scientific and strategic information on drug discovery in tobacco addiction, as a most comprehensive review of the nicotine addiction discovery process;and 2) We will organize a symposium, in conjunction with NIDA program staff, at a major scientific meeting (SRNT or CPDD) and FDA to discuss current clinical endpoints, and the potential and utility for developing biomarkers. We will also host a 2-day summit at TSRI-Scripps Florida to which all awardees of UH2 phase grants, NIDA program officials, leading academic scientists, established and perspective industry partners who may join the PDP, representatives from charitable foundations charged with combating tobacco addiction and smoking- associated disorders, and officials from the State of Florida Department of Health. At the end of this summit, we will identify the optimal partnerships to successfully drive the mission of the MITD PDP. The milestones achieved during the UH3 phase of the MITD PDP are: 1) We will fill a robust preclinical/clinical discovery pipeline based on findings during the UH2 phase;2) By year 3 of the UH3, we will have 1 compound entering Phase II clinical trials;and 3) By year 5 of the UH3, we will have 1 compound entering Phase III clinical trials, and another 1-2 compounds entering Phase II clinical trials. PUBLIC HEALTH RELEVANCE: The burden of disease and negative economic impact of tobacco addiction on society is staggering. It is predicted that ~0.6 billion current smokers worldwide will die from smoking-related illnesses, such as chronic obstructive pulmonary disorder (COPD), lung cancer, and cardiovascular disease. Indeed, if current trends in tobacco use persist, by 2020 smoking will become the largest single health problem worldwide, causing ~8.4 million deaths annually. The World Bank estimates that in high-income countries, smoking-related healthcare accounts for between 6-15% of all healthcare costs, ~$160 billion annually. Smokers who quit before the onset of tobacco-related illness can largely avoid the increased mortality risk. Nevertheless, ~80% of smokers currently attempting to quit will relapse within the first month of abstinence. The development of efficacious smoking cessation aids is considered the most cost-effective intervention possible within a modern health-care system. Product Development Partnerships (PDPs) are a collaborative effort between academia, the pharmaceutical industry and charitable organizations that seek to discover, develop and deliver new medicines. PDPs bridge the gap between research and development for diseases for which there has traditionally been low priority in industry to develop effective therapeutics (small market size etc).